Association between plasma rituximab concentration and the risk of major relapse in antineutrophil cytoplasmic antibody-associated vasculitides during rituximab maintenance therapy

Arthritis Rheumatol. 2023 May 3. doi: 10.1002/art.42556. Online ahead of print.

ABSTRACT

OBJECTIVE: Interindividual variability in response to rituximab remains unexplored in antineutrophil cytoplasmic antibody (ANCA)-associated vasculitides. Rituximab pharmacokinetics (PK) and pharmacodynamics (PD) as well as genetic polymorphisms could contribute to variability. This ancillary study of the MAINRITSAN 2 trial aimed to explore the relationship between rituximab plasma concentration, genetic polymorphisms in PK/PD candidate genes, and clinical outcomes.

METHODS: Patients included in the MAINRITSAN2 trial (NCT01731561) were randomized to receive a 500 mg fixed-schedule RTX infusion or an individually-tailored regimen. Rituximab plasma concentrations at month 3 (C_M3 ) were assessed. DNA samples (n = 53) were genotyped for single nucleotide polymorphisms within 88 putative PK/PD candidate genes. The relationship between PK/PD outcomes and genetic variants was investigated using logistic linear regression in additive and recessive genetic models.

RESULTS: One hundred and thirty-five patients were included. The frequency of underexposed patients (<4 μg/mL) in the fixed-schedule group was statistically lower compared to that in the tailored-infusion group (2.0% vs. 18.0%; p = 0.02, respectively). Low RTX plasma concentration at 3 months (C_M3 <4 μg/mL) was an independent risk factor for major relapse (odds ratio = 6.56; 95% CI 1.26-34.09; p = 0.025) at month 28 (M28). A sensitivity survival analysis also identified C_M3 <4 μg/mL as an independent risk factor for major relapse (Hazard ratio [HR] = 4.81; 95% CI 1.56-14.82; p = 0.006) and relapse (HR = 2.70; 95% CI 1.02-7.15; p = 0.046). STAT4 rs2278940 and PRKCA rs8076312 were significantly associated with C_M3 but not with major relapse onset at M28.

CONCLUSION: These results suggest that drug monitoring could be useful to individualize the schedule of rituximab administration within the maintenance phase. This article is protected by copyright. All rights reserved.

PMID:37134130 | DOI:10.1002/art.42556